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SI2480540T1 - Methylthioninium chloride pentahydrate, preparation and pharmaceutical use thereof - Google Patents

Methylthioninium chloride pentahydrate, preparation and pharmaceutical use thereof Download PDF

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Publication number
SI2480540T1
SI2480540T1 SI201031633T SI201031633T SI2480540T1 SI 2480540 T1 SI2480540 T1 SI 2480540T1 SI 201031633 T SI201031633 T SI 201031633T SI 201031633 T SI201031633 T SI 201031633T SI 2480540 T1 SI2480540 T1 SI 2480540T1
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Slovenia
Prior art keywords
organic solvent
pentahydrate
water
methylthioninium chloride
drying
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SI201031633T
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Slovenian (sl)
Inventor
Rolf Hilfiker
Timo Rager
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Wista Laboratories Ltd.
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Publication of SI2480540T1 publication Critical patent/SI2480540T1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Hospice & Palliative Care (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Steroid Compounds (AREA)
  • Inorganic Compounds Of Heavy Metals (AREA)

Abstract

Substantially pure methylthioninium chloride pentahydrate form A is prepared from methylthioninium chloride by phase equilibration of suspensions, crystallization or solvent evaporation, whereby the water content of the solvent corresponds to a water activity of at least 0.4 at 25° C., and controlled drying of said methylthioninium chloride pentahydrate form A within its stability ranges of humidity, pressure and temperature.

Description

Original document published without description

Claims (11)

Pentahidrat metiltioninijevega klorida, njegova priprava in farmacevtska uporaba Patentni zahtevkiMethylthionine hydrochloride pentahydrate, its preparation and pharmaceutical use Patent claims 1. Postopek za pripravo v bistvu čiste oblike A pentahidrata metiltioninijevega klorida, kjer: a) metiltioninijev klorid suspendiramo v organskem topilu z vsebnostjo vode, ki ustreza aktivnosti vode vsaj 0,4 pri 25 °C, suspenzijo vzdržujemo pri nizki temperaturi in trdno snov izoliramo in sušimo, da odstranimo organsko topilo in kakršen koli prebitek vode iz trdne snovi; b) metiltioninijev klorid raztopimo pri povišanih temperaturah v organskem topilu z vsebnostjo vode, ki ustreza aktivnosti vode vsaj 0,4 pri 25 °C, raztopino ohladimo, oborjeno trdno snov izoliramo in sušimo, da odstranimo organsko topilo in kakršen koli prebitek vode iz trdne snovi; ali c) metiltioninijev klorid raztopimo v organskem topilu z vsebnostjo vode, ki ustreza aktivnosti vode vsaj 0,4 pri 25 °C, in organsko topilo in kakršen koli prebitek vode uparimo do suhega stanja trdne snovi, kjer izvedemo sušenje oblike A pentahidrata metiltioninijevega klorida za odstranitev prebitka vode in/ali topila s sušenjem v toku vlažnega inertnega plina, kjer so sušilne razmere take, da oblika A pentahidrata MTC ni dehidratirana; in kjer ima posušena oblika A pentahidrata metiltioninijevega klorida vsebnost oblike A vsaj 95 % z ozirom na celotno maso metiltioninijevega klorida.A process for the preparation of essentially pure pentahydrate form of methylthionin hydrochloride, wherein: a) methylthioninium chloride is suspended in an organic solvent with a water content corresponding to a water activity of at least 0.4 at 25 ° C, the suspension is maintained at a low temperature and the solid is isolated and dried to remove the organic solvent and any excess water from the solid; b) methylthioninium chloride is dissolved at elevated temperatures in an organic solvent with a water content corresponding to a water activity of at least 0.4 at 25 ° C, the solution cooled, the precipitated solid is isolated and dried to remove the organic solvent and any excess water from the solid ; or c) methylthioninium chloride is dissolved in an organic solvent with a water content corresponding to a water activity of at least 0.4 at 25 ° C, and the organic solvent and any excess of water are evaporated to a dry state of the solid, where drying of the pentahydrate form of methylthioninium chloride for removing excess water and / or solvent by drying in a stream of moist inert gas, wherein the drying conditions are such that the MTC pentahydrate form A is not dehydrated; and wherein the dried form A of the pentahydrate of methylthioninium chloride has a content of Form A of at least 95% with respect to the total weight of methylthioninium chloride. 2. Postopek po zahtevku 1, kjer je organsko topilo mešljivo z vodo.The process of claim 1, wherein the organic solvent is miscible with water. 3. Postopek po zahtevku 1 ali 2, kjer je parni tlak organskega topila višji od parnega tlaka vode.A process according to claim 1 or 2, wherein the vapor pressure of the organic solvent is higher than the vapor pressure of the water. 4. Postopek po katerem koli od zahtevkov 1-3, kjer ima organsko topilo, uporabljeno v varianti a) ali b) postopka, zmogljivost raztapljanja manj kot 20 g/1 za obliko A pentahidrata metiltioninijevega klorida pri sobni temperaturi in kjer ima organsko topilo, uporabljeno v varianti c) postopka, zmogljivost raztapljanja več kot 20 g/1 za obliko A pentahidrata metiltioninijevega klorida pri sobni temperaturi.A process according to any one of claims 1 to 3, wherein the organic solvent used in variant a) or b) of the process has a dissolution capacity of less than 20 g / l for the pentahydrate form of methylthionin hydrochloride at room temperature and wherein the organic solvent, used in the variant c) of the process, a dissolution capacity of more than 20 g / l for the form of pentahydrate methylthionin hydrochloride at room temperature. 5. Postopek po katerem koli od zahtevkov 1-4, kjer izvedemo izolacijo proizvoda v varianti a) ali b) postopka pri temperaturi, ki ni višja od 40 °C.A process according to any one of claims 1-4, wherein the isolation of the product in variant a) or b) of the process is carried out at a temperature not higher than 40 ° C. 6. Postopek po katerem koli od zahtevkov 1-5, kjer je organsko topilo izbrano iz skupine, ki jo sestavljajo metanol, etanol, 1-propanol, 2-propanol, 2-metil-2-propanol, acetonitril, tetrahidrofuran, 1,4-dioksan in njihove zmesi.The process according to any one of claims 1-5, wherein the organic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, acetonitrile, tetrahydrofuran, 1.4 -doxane and mixtures thereof. 7. Postopek po katerem koli od zahtevkov 1-6, kjer vsebnost vode tekoče faze ne presega 50 mas. %, bolj prednostno 20 mas. % z ozirom na celotno maso tekoče faze.The process according to any one of claims 1-6, wherein the water content of the liquid phase does not exceed 50 wt. %, more preferably 20 wt. % with respect to the total mass of the liquid phase. 8. Postopek po katerem koli od zahtevkov 1-7, kjer sušenje v toku plina prednostno izvedemo pri temperaturi, ki ni višja od 40 °C, in pri relativni vlažnosti plina, ki ni pod 30 %.The process according to any one of claims 1-7, wherein drying in a gas stream is preferably carried out at a temperature not higher than 40 ° C and at a relative humidity of less than 30% of the gas. 9. Metoda za sušenje oblike A pentahidrata MTC za odstranitev prebitne vode in/ali topila s sušenjem v toku vlažnega inertnega plina, kjer so sušilne razmere take, da oblika A pentahidrata MTC ni dehidratirana in kjer ima posušena oblika A pentahidrata metiltioninijevega klorida vsebnost oblike A vsaj 95 % z ozirom na celotno maso metiltioninijevega klorida.Method for drying the MTC form A pentahydrate for removing excess water and / or solvent by drying in a stream of moist inert gas, wherein the drying conditions are such that the MTC pentahydrate form A is not dehydrated and wherein the dried form A of the pentahydrate of methylthionin hydrochloride has a content of Form A at least 95% with respect to the total weight of methylthioninium chloride. 10. Metoda po zahtevku 9, kjer izvedemo sušenje pri temperaturi, ki ni višja od 40 °C, ali temperaturi, ki ni višja od 30 °C, ali temperaturi, ki ni višja od 25 °C.The method of claim 9, wherein drying is carried out at a temperature of not greater than 40 ° C or a temperature of not higher than 30 ° C or a temperature of not more than 25 ° C. 11. Metoda po katerem koli od zahtevkov 9-10, kjer relativna vlažnost plina ni pod 30 %.The method of any one of claims 9-10, wherein the relative humidity of the gas is not below 30%.
SI201031633T 2009-09-24 2010-09-23 Methylthioninium chloride pentahydrate, preparation and pharmaceutical use thereof SI2480540T1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US24537209P 2009-09-24 2009-09-24
PCT/IB2010/002543 WO2011036561A2 (en) 2009-09-24 2010-09-23 Process
EP10771180.6A EP2480540B1 (en) 2009-09-24 2010-09-23 Methylthioninium chloride pentahydrate, preparation and pharmaceutical use thereof

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US (1) US8901296B2 (en)
EP (1) EP2480540B1 (en)
JP (2) JP5918136B2 (en)
KR (1) KR101728574B1 (en)
CN (1) CN102666510B (en)
AU (1) AU2010299574B2 (en)
BR (1) BR112012006626B8 (en)
CA (1) CA2773306C (en)
DK (1) DK2480540T3 (en)
ES (1) ES2659091T3 (en)
HR (1) HRP20180347T1 (en)
MX (1) MX2012003035A (en)
MY (1) MY161463A (en)
PL (1) PL2480540T3 (en)
PT (1) PT2480540T (en)
SI (1) SI2480540T1 (en)
WO (1) WO2011036561A2 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9192611B2 (en) * 2010-11-30 2015-11-24 Wista Laboratories Ltd. Formulations comprising methylthioninium chloride
AU2017301966B2 (en) 2016-07-25 2022-09-22 TauRx Therapeutics Management Ltd Administration and dosage of diaminophenothiazines
GB201614834D0 (en) * 2016-09-01 2016-10-19 Wista Lab Ltd Treatment of dementia
EP3826639B1 (en) 2018-07-26 2024-08-21 WisTa Laboratories Ltd. Optimised dosage of diaminophenothiazines in populations
EP4531863A1 (en) 2022-05-31 2025-04-09 WisTa Laboratories Ltd. Treatment of neurodegenerative disorders utilising methylthioninium (mt)-containing compounds
EP4590306A1 (en) 2022-09-21 2025-07-30 Yin Sze Loh Oral formulation of diaminophenothiazines and methods of making and using the same in the treatment and/or prevention of diseases

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* Cited by examiner, † Cited by third party
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US20030124028A1 (en) * 2001-08-10 2003-07-03 Carlson Eric D. Apparatuses and methods for creating and testing pre-formulations and systems for same
US7790881B2 (en) * 2004-09-23 2010-09-07 Wista Laboratories Ltd. Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC)
PT1799662E (en) * 2004-09-23 2013-07-09 Wista Lab Ltd Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (mtc)
CN109384741B (en) 2006-03-29 2023-01-06 维斯塔实验室有限公司 3,7-diamino-10H-phenothiazine compound salt and application thereof
ES2689029T3 (en) * 2009-09-24 2018-11-08 Wista Laboratories Ltd. Crystalline Methylthioninium Chloride Hydrates - Part 2

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Publication number Publication date
PT2480540T (en) 2018-02-16
EP2480540A2 (en) 2012-08-01
HRP20180347T1 (en) 2018-04-06
BR112012006626A2 (en) 2016-05-03
JP2016074699A (en) 2016-05-12
CN102666510A (en) 2012-09-12
DK2480540T3 (en) 2018-01-22
WO2011036561A8 (en) 2012-04-19
CN102666510B (en) 2016-09-14
WO2011036561A2 (en) 2011-03-31
KR20120099410A (en) 2012-09-10
US20120289499A1 (en) 2012-11-15
PL2480540T3 (en) 2018-05-30
MY161463A (en) 2017-04-14
ES2659091T3 (en) 2018-03-13
BR112012006626B8 (en) 2021-05-25
KR101728574B1 (en) 2017-04-19
CA2773306A1 (en) 2011-03-31
AU2010299574A1 (en) 2012-03-29
AU2010299574B2 (en) 2013-09-26
WO2011036561A3 (en) 2011-05-19
EP2480540B1 (en) 2017-11-29
JP2013505926A (en) 2013-02-21
CA2773306C (en) 2018-04-24
BR112012006626B1 (en) 2021-04-20
US8901296B2 (en) 2014-12-02
JP5918136B2 (en) 2016-05-18
MX2012003035A (en) 2012-06-12

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